Obesity, which often associates with other metabolic disorders, has become a global threat to human health. In the United States, over two-thirds of adults are overweight and one-third is obese. The most serious and frequent major complications of obesity are atherosclerosis and “heart attack”.
Metabolic syndrome (Sutherland, et al., Metabolic Syndrome and Related Disorders 2:82-104 (2004); Esposito, et al., Nutr. Metab. Cardiovasc. Dis. 14:228-232 (2004)), relates to obesity and is characterized by a group of metabolic risk factors including: 1) abdominal obesity (excessive fat tissue in and around the abdomen); 2) atherogenic dyslipidemia (high triglycerides; low HDL cholesterol and high LDL cholesterol); 3) elevated blood pressure; 4) insulin resistance or glucose intolerance; 5) a prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor-1 in the blood); and 6) a proinflammatory state (e.g., elevated CRP in the blood). Metabolic syndrome has become increasingly common in developed countries and is closely associated with risk of coronary heart disease (Malik, et al., Circulation 110:1245-1250 (2004); Irabarren, et al., J. Am. Coll. Cardiol. 48:1800-1807 (2006)). Accumulating evidence suggests that the key features of metabolic syndrome are closely associated with chronic inflammation characterized by macrophage accumulation, increased cytokine production, and activation of a network of inflammatory signaling pathways.
Cardiometabolic syndrome includes obesity-related metabolic disorders and atherosclerosis. Cardiometabolic disorders also promote arterial and valvular calcification which may lead to devastating clinical complications: acute myocardial infarction and aortic stenosis. In addition, diabetes causes chronic kidney disease that also leads to cardiovascular ectopic calcification and acute myocardial infarction. Collectively, several major components of the cardiometabolic syndrome, developed via interrelated mechanisms, enhance each other through local or systemic inflammation.
The NOTCH signaling pathway has been identified as playing an important role in many diverse biological functions, including cellular differentiation and proliferation (see U.S. Pat. No. 6,703,221). Mutations that increase NOTCH signaling have been associated with the development of leukemia and inhibitors of NOTCH are being studied for their potential use in the treatment of neurological diseases and cancer (Artavanis-Tsakonas, et al., Science. 284:770-776 (1999); Wang, et al., Science 306:269-271 (2004); Stockhausen, et al., Br. J. Cancer 92:751-759 (2005); Van Es, et al., Nature 435:959-963 (2005)).
The NOTCH pathway is activated by four different transmembrane receptor subtypes (designated as NOTCH-1-NOTCH-4) that rely upon regulated proteolysis. Expression patterns of NOTCH depend on cell type. Following ligand binding, the receptor undergoes sequential cleavage by metalloproteases of the ADAM family (Bru, et al., Mol. Cell 5:207-216 (2000); Mumm, et al., Mol. Cell 5:197-206 (2000)) and the presenilin-dependent gamma-secretase (Selkoe, et al., Annu. Rev. Neurosci. 26:565-97 (2003); De Strooper, et al., Nature 398:518-522 (1999)). The final proteolytic cleavage step permits the intracellular domain of the NOTCH receptor to translocate to the cell nucleus where it interacts with transcription factors to induce target gene expression.
In the cell nucleus, the NOTCH intracellular domain undergoes ubiquitilation. Proteolytic processing of the NOTCH precursor protein by furin-protease and its trafficking to the cell membrane also determine turnover and availability of receptors, and, in turn, activation of this signaling pathway. Altered glycosylation of the Notch extracellular domain by Fringe protein family members may also modify efficiency of ligand binding.
As mentioned above, inhibitors of NOTCH, particularly gamma-secretase inhibitors, have received a great deal of attention as possible therapeutic agents for the treatment of neurological diseases (especially Alzheimer's disease) and cancer (especially leukemia). The therapeutic use of these agents in treating or preventing obesity or metabolic syndrome would represent a clear advance in medicine and public health.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.